Resting-state global brain activity affects early β-amyloid accumulation in default mode network

It remains unclear why β-amyloid (Aβ) plaque, a hallmark pathology of Alzheimer’s disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aβ accumulation in the DMN at the early stage of Aβ pathology was associated with the preferential reduction of global brain activity in the same regions. This can be partly explained by its failure to reach these regions as propagating waves. Together, these findings highlight the important role of resting-state global brain activity in early preferential Aβ deposition in the DMN.


Figure S3
Higher-and lower-order masks.We derived the higher-order mask consisting of the DKT-68 parcels 1 belonging to default mode network (DMN) and frontoparietal network (FPN), and the lower-order mask including those the somatosensory and visual parcels.These networks were defined by Yeo's 7 network parcellation 4 (refer to Methods for details).We applied the two-sample t-test (two-sided) between the stage S2: CSF+/PET-and S1: CSF-/PET-(D), as well as between S3: CSF+/PET+ and S2: CSF+/PET-(E) (t = 2.1 corresponding to P = 0.05).These between-stage differences were consistent with the previous study 5 that the cortical Aβ accumulated more rapid at the higherorder regions from S1: CSF-/PET-to S2: CSF+/PET-and then at the lower-order networks from S2: CSF+/PETto S3: CSF+/PET+.(F) We also extracted the cortical Aβ accumulated at higher-or lower-order masks (see Figure S3) to quantitatively compare the cortical Aβ changes at the two masks (adjusted for age and gender; twosample t-test, two-sided).The notch box plot showed the cortical Aβ at higher-order regions accumulated more from the first stage to the second stage (P < 0.01), while the Aβ at lower-order ones increased more steadily across stages (The sample size for S1, S2, and S3 are N = 42, N =19, and N = 51, respectively).The bottom and top edges and the central line of the boxes represent the first and third quartiles and the median respectively, and the whiskers represent the minimum and maximum.The "notches" on the boxes delineate the 95% conference interval for the median.Asterisks represent significant level (*: 0.01 < P < 0.05; **: 0.001 < P < 0.01; and ***: P < 0.001).
Source data are provided as a Source Data file.CSF Aβ42.The tilted bands (top-left panel) showed the segment-mean DMN-to-SM pattern that propagates from the higher-order DMN regions (align the principal gradient (PG)) to the lower-order somatosensory network.The detailed spatial patterns of cortical co-activation at three representative temporal phases are shown in the right panels (within the dashed rounded rectangles).Both the time-position graphs and spatial maps from the two subgroups showed a much weaker activation at the higher-order DMN in low-level CSF Aβ42 subjects at the early propagation phase.(C) A two-sample t-test (two-sided) was used to test the difference between the DMN-to-SM propagation segments from the highest and lowest CSF Aβ42 subjects.The results showed the highest CSF Aβ42 subjects had stronger higher-(DMN) and lower-order activation at around -3s and +3.6s, respectively, but these high-level CSF Aβ42 subjects appeared to be with weaker DMN activation at +3.6s compared with low-level CSF Aβ42 ones (bottom-right panel).The hot color in the bottom-left panel showed that the activation in the high-level CSF Aβ42 subjects was significantly stronger (P < 0.05, i.e., t > 2.1) than that in the low-level CSF Aβ42 ones.
Source data are provided as a Source Data file.The "notches" on the boxes delineate the 95% conference interval for the median.The sample size of each subgroup is shown on the notch boxes.(C) When the minimum gBOLD-CSF cross-correlations were taken as the new coupling metrics, a little more abrupt decrease was found across the severities than the previous coupling (pordinal = 0.061; two-sample, two-sided t-test was also applied).Source data are provided as a Source Data file.

Figure S2 .
Figure S2.(A-C) The association between cortical amyloid-beta (Aβ) level and the three cerebrospinal fluid

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Figure S4 Surface maps of two-year cortical amyloid-beta (Aβ) change at each stage of Aβ pathology

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Figure S5 Region-specific association between two-year amyloid-beta (Aβ) change and the rBOLD-CSF (regional BOLD-cerebrospinal fluid) coupling.For each of DKT-68 parcels 1 , we correlated the two-year Aβ

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Figure S6 Early accumulators with distinct level of cerebrospinal fluid (CSF) amyloid-beta 42 (Aβ42) have

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Figure S8 The associations between fMRI measures and various Alzheimer's disease (AD) protein markers

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Figure S9 The associations between fMRI measures and various Alzheimer's disease (AD) protein markers

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Figure S10 Subject-specific lags would not either variate among different disease conditions (i.e.,

Figure S11
Figure S11The replication of major correlation results in Figure3Dwith extracting the regional BOLD signals in native space for each subject (Two-sided Spearman's correlation).Source data are provided as a Source Data file.

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Figure S12 The associations between fMRI measures and various Alzheimer's disease (AD) protein

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Figure S13 Excluding the subjects scanned with different repetition time (TRs) and echo time (TEs) make

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Figure S14 The associations between fMRI measures and various Alzheimer's disease (AD) protein